Depression heterogeneity and its biological underpinnings: towards immuno-metabolic depression

Abstract Epidemiological evidence indicates dysregulated homeostatic biological pathways in depressed patients, such as increased inflammation and disrupted energy-regulating neuroendocrine signaling (e.g. leptin, insulin). Alterations in these biological pathways may explain the considerable comorbidity between depression and cardiometabolic conditions (e.g. obesity, metabolic syndrome, diabetes) and represent a promising target for intervention. This review will describe how immuno-metabolic dysregulations vary as a function of depression heterogeneity by illustrating that such biological dysregulations: 1) map more consistently to “atypical” behavioral symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis); and 2) may moderate the antidepressant effects of standard or novel (e.g. anti-inflammatory) therapeutic approaches. These lines of evidence will be integrated in a conceptual model of immuno-metabolic depression emerging from the clustering of immuno-metabolic biological dysregulations and specific behavioral symptoms. The review will finally elicit questions to be answered by future research and will describe how the immuno-metabolic depression dimension could be used to dissect depression’s heterogeneity and potentially to match subgroup of patients to specific treatments with higher likelihood of clinical success.